An Open, Single Centre, Randomised, Parallel Group Study to Investigate Three Different Immunosuppressive Regimens

This study is designed to show similar efficacy but a different adverse event profile between the three regimens. Its main purpose is to provide more information, if steroid free immunosuppressive treatment is a valuable alternative in the treatment of de novo kidney transplant recipients and that it is possible to withdraw calcineurin inhibitors after 3 months in this steroid free protocol. A secondary rationale of the study is to compare sirolimus with everolimus directly to better differentiate these two mTOR-inhibitors in terms of compound-specific effects and class-effects. This should allow for early conclusions on the usage of these two mTOR-inhibitors in CNI-free regimens.

Basis for this study are the following hypotheses regarding the first 6 months of treatment following kidney transplantation:

• Similar graft function in the three treatment groups after 6 months
• No difference in graft and patient survival in the three groups
• No differences in incidence of first, total number, type of acute rejections, and number of anti-rejection treatments in the three groups
• No differences in number of patients successfully withdrawn from calcineurin inhibitor in the sirolimus and everolimus arm, respectively
• A different adverse event profile with regard to the incidence of dyslipidemias, impaired fasting glucose, new onset diabetes mellitus, de novo post-transplant insulin dependency, histological signs of calcineurin inhibitor toxicity, and tubulointerstitial nephrotoxicity in the three groups. In addition to this the incidence of mTOR-inhibitor specific adverse events will be analysed.

These hypotheses are the basis for the study objectives.

Inclusion criteria

• Male or female patients between 18 and 75 years of age, regardless of race.
• Female patients of child bearing age agree to maintain effective birth control practice during the study.
• Patient has end stage kidney disease and is a suitable candidate for primary renal transplantation or retransplantation as assessed by the transplantation centre.
• Patient has been fully informed and has given written or independent person witnessed oral informed consent.

Exclusion criteria

• in Patient is pregnant or breastfeeding.
• Patient has a low immunological risk constellation, defined by receiving a kidney from a HLA-identical related living donor.
• Patient has a high immunological risk constellation, defined as having donor specific HLA-antibodies and/or having a previous graft survival shorter than 3 years due to rejection.
• Patient and donor have a positive T or B-cell crossmatch.
• Patient and donor are ABO incompatible.
• Age of donor > 75 years.
• Cold ischemia time > 36 hours.
• Patient has leucopenia, defined as having at transplantation less than 3000/mm3 leukocytes.
• Patient has thrombocytopenia, defined as having at transplantation less than 75000/mm3 thrombocytes.
• Patient is allergic or intolerant to cremophor RH 60 or structurally related compounds, steroids, everolimus, tacrolimus, Sirolimus or EC-MPS.
• Patient or donor is known to be HIV positive.
• Patient has significant liver disease, defined as having during the past 28 days continuously ASAT (SGOT) and/or ALAT (SGPT) levels greater than 3 fold of the upper value of the normal range of the investigational site.
• Patient with malignancy or history of malignancy ≤ 2 years, except non metastatic basal or squamous cell carcinoma of the skin that has been treated successfully.
• Patient has significant, uncontrolled concomitant infections and/or severe diarrhea, vomiting, or active peptic ulcer.
• Patient is taking or has been taking an investigational drug in the past 28 days.
• Patient has previously received or is receiving another organ transplant other than kidney.
• Patient is unlikely to comply with the visits schedule the protocol.